Disseminated C. albicans infection in patients who have a weakened immune system is life-threatening. In hospitals 40% of bloodstream infections (candidemia) are caused by Candida spp. Despite the availability of several anti-fungal drugs, invasive candidiasis still has a high mortality rate ranging from 45 to 75%. The high morbidity and mortality associated with disseminated candidiasis are mainly due to the lack of early and accurate diagnostic tools, the limited anti-fungal drugs, and the emergence of drug resistance, thus highlighting the need to further understand host-pathogen interactions and the mechanisms of immune resistance to fungal spread, and to develop alternative immune-based strategies to combat candidemia. In normal hosts, C. albicans is controlled after activation of innate immune cells via cell surface pattern recognition receptors (PRRs) such as TLR2 and C-type lectin receptors (CLRs) that detect the infecting fungi. The CLRs Dectin-1 and Dectin-2/3 recognize C. albicans yeast cells and hyphae by binding to the surface ?-glucans and ?- mannans of the two fungal forms, respectively. Recognition of these molecules results in release of inflammatory cytokines from innate immune cells, which is critical for anti-fungal immunity. The mechanisms that control this CLR-mediated innate immune response to fungal infection are completely unknown. Our preliminary results showed that bone marrow-derived macrophages (BMDMs) from Cblb-/- mice infected with C. albicans yeast and hyphae produce more inflammatory cytokines than do BMDMs from wild type (WT) mice. This response involves signaling via Dectin-1, -2, and/or -3 but not via the TLRs. This finding suggests that Cbl-b acts through the Dectin CLRs but not the TLRs in macrophages. Consistent with this notion, BMDMs from Cblb-/- mice have impaired Dectin-1, -2, and -3 degradation upon interaction with C. albicans yeast and hyphae. In support of this finding, Dectin-1 undergoes poly-ubiquitination in macrophages upon infection with C. albicans yeasts, whereas this ubiquitination is abrogated in BMDMs lacking Cbl-b. Furthermore, Cblb-/- mice are protected from infection with a lethal dose of C. albicans. Based on these results, we hypothesize that during C. albicans infection, Cbl-b is recruited to Dectin CLRs, and this targets Dectins for ubiquitination which dampens CLR-mediated innate immune responses against fungi. To test this hypothesis, we propose to determine (1) whether and how Cbl-b regulates Dectin down-modulation via protein ubiquitination in vitro; and (2) whether Cbl-b dampens host effective responses against C. albicans mediated by the Dectin family of CLRs. Successful completion of this project will reveal a previously unknown host defense mechanism and provide molecular insight into the host defense machinery and ultimately facilitate the identification of candidate targets for appropriate modulation of anti-fungal responses and therapeutic options.